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Drug target prioritization for new targets and drug repurposing of existing drugs for COVID-19 treatment are urgently needed for the current pandemic. COVID-19 drugs targeting human proteins will potentially result in less drug resistance but could also exhibit unintended effects on other complex diseases. Here we pooled 353 candidate drug targets of COVID-19 from clinical trial registries and the literature and estimated their putative causal effects in 11 SARS-CoV-2 related tissues on 622 complex human diseases. By constructing a disease atlas of drug targets for COVID-19, we prioritise 726 target-disease associations with evidence of causality using robust Mendelian randomization (MR) and colocalization evidence (http://epigraphdb.org/covid-19/ctda/). Triangulating these MR findings with historic drug trial information and the druggable genome, we ranked and prioritised three genes DHODH, ITGB5 and JAK2 targeted by three marketed drugs (Leflunomide, Cilengitide and Baricitinib) which may have repurposing potential with careful risk assessment.

Objective: Alzheimers disease (AD) has several known genetic determinants, yet the mechanisms through which they lead to disease onset remain poorly understood. This study aims to estimate the effects of genetic liability to AD on plasma metabolites measured at seven different stages across the life course. Methods: Genetic and metabolomic data from 5,648 offspring from the Avon Longitudinal Study of Parents and Children birth cohort were used. Linear regression models examined the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18 and 25 years of age. Two hundred twenty-nine metabolites were studied, most relating to lipid/lipoprotein traits. Two-sample Mendelian randomization was performed using summary statistics from age-stratified genome-wide association studies (GWAS) of the same metabolites for 118,466 participants from the UK Biobank, to examine the persistence of any AD liability effects into late adulthood. Results: The GRS including the APOE4 isoform demonstrated the strongest positive associations for cholesterol-related traits per doubling of genetic liability to AD, e.g., for low-density lipoprotein cholesterol (LDL-C) at age 25yrs (0.12 SD; 95% CI 0.09, 0.14), with similar magnitudes of association across age groups in ALSPAC. In the UK Biobank, the effect of AD liability decreased with age tertile for several lipid traits (e.g., LDL-C, youngest: 0.15 SD; 95% CI 0.07, 0.23, intermediate: 0.13 SD; 95% CI 0.07, 0.20, oldest: 0.10 SD; 95% CI 0.05, 0.16). Across both cohorts, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) attenuated as age increased. Fatty acid metabolites also demonstrated positive associations in both cohorts, though smaller in magnitude compared with lipid traits. Sensitivity analyses indicated that these effects were driven by the APOE4 isoform. Conclusions: These results support a profound influence of the APOE4 isoform on circulating lipids and fatty acids from early life to later adulthood. Such lipid and fatty acid traits may be implicated in early AD pathogenesis and warrant further investigation as potential targets for preventing the onset of AD.

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